The present invention relates to oral sustained release pharmaceutical preparations in the form of microparticles of granular drug, a pH controlled material, and a diffusion membrane. More particularly, the present invention relates to using PH controlled material to produce a formulation having a sustained release of drug whereby the release is independent of the pH environment.
As is well known, the maximum time of effectiveness in many pharmaceutical preparations, particularly those containing a drug such as gemfibrozil, ibuprofen, indomethacin, and naproxen, etc. is only a few hours because of biological modification and/or elimination of the medication in the body. Consequently, repeated dosages must be taken at frequent intervals to obtain long term therapeutic levels of drug. Furthermore, these drugs usually dissolve readily in the digestive juices and the total dosage is immediately fed into the blood stream. After high initial peak concentrations, the level of drug in the blood stream constantly decreases because of the biological elimination, so there is little or no therapeutic effect at the end of the period between dosages. As a result, the therapeutic effect fluctuates between dosages corresponding to the peaks and valleys in the level of drug in the blood as commonly measured by trough to peak ratios. Many attempts have been made to control the release of the medication to minimize the trough to peak ratios.
However, most conventional sustained-release formulations of drugs which contain acid and/or amine functionalities have a release rate that is strongly dependent on pH. Since the pH of the human gastro-intestinal tract ranges from about 1 to 7.5 in a variable manner, the drug release is erratic. In addition, conventional sustained release formulations of drugs that contain acid or amine functionalities are poorly bioavailable when local gastro-intestinal pH causes the drug to be poorly soluble. Furthermore, conventional formulations such as these risk the rapid release or dumping of drugs when local gastro-intestinal pH causes excessively rapid drug dissolution. Consequently, a sustained and uniform release of drug for a period of at least 12 to 24 hours has not previously been possible.
Still, it has been known that various polymers can be used with the drug core and further, it has been known that a control coat can be formed over this core. For example, Mousimer et al in U.S. Pat. No. 4,205,060 forms a microcapsule comprising a core containing a water soluble salt of a medicament and a polymer, e.g. the salt of a medicament containing an amino-group and a carboxyl group containing polymer, and a sheath of a water-insoluble film forming polymer e.g. ethyl cellulose. Likewise, Fukui et al in U.S. Pat. No. 4,772,475 discloses a pharmaceutical controlled-release individual units or multiple units formulation comprising a granulation product of a drug and a release controlling agent such as acrylic acid polymers, acrylic acid copolymers and mixtures thereof with cellulose derivatives and crystalline cellulose, with a sheath formed by conventional encapsulation. See also, Phillips et al, U.S. Pat. No. 4,816,264 which discloses a drug core containing a hydrocolloid gelling polymer such as hydroxyethyl cellulose and an Eudragit E-30-D sheath. However, when used for drugs with acid or amine functionalities all of these use conventional sustained release formulations which are not pH independent and thus, have the aforementioned non-uniform drug release problems.
Thus, there remains a need for a pharmaceutical preparation that releases drug independent from the pH of the environment and therefore, is capable of providing a uniform and sustained release of drug for a period of at least 12 to 24 hours.